Metabolites of arachidonic acids are involved in the pathogenesis of many acute and chronic inflammatory conditions. The class of lipoid metabolites of arachidonic acid is generated through a series of enzyme actions. The most important enzyme in terms of treatment is prostaglandin G/H synthase, i.e. cyclooxygenase (COX), which catalyzes the production of various angiotensin and inflammatory substances, such as prostaglandin (PGE2, PGD2, PGF2), prostacyclin (PGI2), and thromboxane (TXA2), etc.
Non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used for treating pain and arthritis due to their significant anti-inflammatory and analgesic effects. NSAIDs work mainly by inhibiting cyclooxygenase (COX), i.e. prostaglandin G/H synthase (PGHs), thereby inhibiting the metabolism of arachidonic acid into prostaglandins. Prostaglandin, especially prostaglandin PGE2, is a major mediator contributing to pain, fever and the other symptoms associated with inflammation, and is the major arachidonic acid detected when inflammation occurs. Inhibition of prostaglandin biosynthesis has been proved to be an important target of anti-inflammatory drugs. However, therapeutic use of traditional non-steroidal anti-inflammatory drugs is significantly limited due to their side effects of life-threatening ulcers and renal toxicity. Corticosteroid drugs can serve as alternatives for NSAIDs, however, their long-term use will produce serious side effects as well.
In early 1990s, cyclooxygenase was found existing in two enzyme types, COX-1 and COX-2. COX-1 is present in many normal tissues such as stomach, kidney and platelets. Gastrointestinal and renal side effects caused by NSAIDs are resulted from COX-1 inhibition. COX-2 is inducible. When induced by a series of inflammatory factors or cytokines, COX-2 can be expressed in large quantity in many tissues, such as macrophages, bone cells, fibroblasts and endothelial cells.
The discovery of COX-2 makes synthesis of selective COX-2 inhibitors possible. The highly selective COX-2 inhibitors greatly reduced COX-1 inhibition, thereby reducing the ulcer toxicity, and improving the gastrointestinal tolerability of these drugs. The present disclosure discloses a novel class of selective COX-2 inhibitors.